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Metabolism of Antioxidant and Chemopreventive Ellagitannins from Strawberries, Raspberries, Walnuts, and Oak-Aged Wine in Humans: Identification of Biomarkers and Individual Variability
Abstract
Ellagitannins (ETs) are dietary polyphenols, containing ellagic acid (EA) subunits, with antioxidant and cancer chemopreventive activities that might contribute to health benefits in humans. However, little is known about their metabolic fate. We investigate here the metabolism of different dietary ETs and EA derivatives in humans. Forty healthy volunteers were distributed in four groups. Each group consumed, in a single dose, a different ET-containing foodstuff, i.e., strawberries (250 g), red raspberries (225 g), walnuts (35 g), and oak-aged red wine (300 mL). After the intake, five urine fractions (F) were collected at 8 (F1), 16 (F2), 32 (F3), 40 (F4), and 56 (F5) h. Neither ETs nor EA were detected in urine after LC-MS/MS analysis. However, the microbial metabolite 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (urolithin B) conjugated with glucuronic acid was detected along the fractions F3-F5 in all of the subjects, independently of the consumed foodstuff. The mean percentage of metabolite excretion ranged from 2.8 (strawberries) to 16.6% (walnuts) regarding the ingested ETs. Considerable interindividual differences were noted, identifying "high and low metabolite excreters" in each group, which supported the involvement of the colonic microflora in ET metabolism. These results indicate that urolithin B (a previously described antiangiogenic and hyaluronidase inhibitor compound) is a biomarker of human exposure to dietary ETs and may be useful in intervention studies with ET-containing products. The antioxidant and anticarcinogenic effects of dietary ETs and EA should be considered in the gastrointestinal tract whereas the study of potential systemic activities should be focused on the bioavailable urolithin B derivatives.
... EA has a variety of health benefits related to the protection it provides from oxidative stress [20,188,[190][191][192]. EA is reported to have a low water solubility and bioavailability, however, when it is converted to urolithin A (UA) by the gut microbiome, UA retains the biological activities of EA and has high solubility and bioavailability ( Figure 8). Urolithins are biologically active compounds exhibiting strong antioxidant effects [193][194][195][196] and anti-inflammatory [196,197] and neuroprotective properties [100,198]. Punicalagin, chebulinic acid, and chebulagic acid are complex polyphenolic ellagitannins that occur in pomegranate and are degraded to form EA by the gut microbiome ( Figure 8). ...
... Punicalagin, chebulinic acid, and chebulagic acid are complex polyphenolic ellagitannins that occur in pomegranate and are degraded to form EA by the gut microbiome ( Figure 8). EA is further degraded to the urolithins; these are not synthesised or generated by mammalian cells and have antioxidant and anti-inflammatory properties [20,100,[190][191][192][193][194][195][196][197][198]. Panduratin A is an antioxidant polycyclic chalcone phenolic that has also been identified in pomegranate and in the Thai medicinal plant Boesenbergia rotunda that has reported antiviral properties against SARS-CoV-2 [199]. ...
... ellagitannins that occur in pomegranate and are degraded to form EA by the gut microbiome ( Figure 8). EA is further degraded to the urolithins; these are not synthesised or generated by mammalian cells and have antioxidant and anti-inflammatory properties [20,100,[190][191][192][193][194][195][196][197][198]. Panduratin A is an antioxidant polycyclic chalcone phenolic that has also been identified in pomegranate and in the Thai medicinal plant Boesenbergia rotunda that has reported antiviral properties against SARS-CoV-2 [199]. ...
Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.
... 20 Thus, cells of tissues and organs in the body may not directly interact with ellagitannins and ellagic acid. In contrast, it is widely reported that UB and its derivatives can reach the plasma concentration of micromolar level 21 and exert biological activities in vivo, [22][23][24][25] revealing that UB has higher bioavailability than ellagitannin and ellagic acid. 21 In this study, the effect of UB on osteoclast differentiation induced by bone marrow-derived macrophages (BMMs) and RAW264.7 cells in vitro was investigated. ...
... In contrast, it is widely reported that UB and its derivatives can reach the plasma concentration of micromolar level 21 and exert biological activities in vivo, [22][23][24][25] revealing that UB has higher bioavailability than ellagitannin and ellagic acid. 21 In this study, the effect of UB on osteoclast differentiation induced by bone marrow-derived macrophages (BMMs) and RAW264.7 cells in vitro was investigated. And OVX model mice was established to study the therapeutic efficacy of UB on osteoporosis. ...
... Some researchers have reported that the intestinal flora metabolite N-acylamide was a ligand analog of G protein-coupled receptors and can modulate glucose homeostasis. 9 Given that ellagitannin, the precursor of UB, has been reported to alleviate osteoporosis in castrated mice, 18,19 and UB is more bioavailable, 21 we explored the effect of UB on osteoclasts and its mechanism of action. ...
Objectives:
The main target of current drugs for alleviating bone loss is osteoclasts. However, the long-term application of such drugs will also cause side effects. Therefore, it is of great need to develop new and safer therapeutics for osteoporosis. In recent years, drug development based on gut microbiota has gradually attracted attention. This manuscript investigates the inhibitory effect of urolithin B (UB) on osteoclastogenesis and differentiation in vitro and in ovariectomized (OVX) mice.
Materials and methods:
CCK-8 was used to analyse the cytotoxicity of UB; BMMs cells were differentiated into osteoclasts by RANKL, and respectively treated with 1, 5, and 25 μmol/L UB during this process. After one week of intervention, tartrate-resistant acid phosphatase (TRAP) staining was used to analyse the number and average area of osteoclasts. F-actin staining and immunofluorescence staining were conducted to evaluate the morphology and function of osteoclasts. Bone resorption function of osteoclasts was detected by Pit Formation Assay. The expression of osteoclast-related protein genes in RAW264.7 cells were investigated via western blot and RT-PCR assays. Western blot analysis of RANKL-mediated activation of MAPK/NF-κB pathway after 0, 5, 15, 30, 60 min of intervention. For in vivo experiments, OVX mice received intraperitoneal injection of 10, 50 mg/kg every two days, 8 weeks later, the femurs of mice were taken for morphological analysis, and the serum content of CTX-1, a bone metabolism index, was analysed.
Results:
UB could inhibit the osteoclast differentiation of rankl-induced bone marrow macrophages (BMMs) and RAW264.7 cells in vitro, suppress the uptake activity of hydroxyapatite and expression of osteoclast-related gene MMP9, CTSK, NFATc1 and c-fos. Furthermore, UB repressed the rankl-induced phosphorylation and degradation of IκB and the phosphorylation of P65 in the NF-κB pathway of RAW264.7 cells, and also down-regulated the phosphorylation level of ERK in the MAPK pathway. For in vivo studies, UB-treated OVX mice showed more significant improved various parameters of distal femur compared with the control group, with fewer NFATc1, MMP9 and TRAP-positive osteoclasts in bone tissues, and less serum content of CTX-1.
Conclusion:
Urolithin B attenuated bone loss in OVX mice by inhibiting the formation and activation of osteoclasts via down-regulation of the ERK/NF-κB signalling pathway.
... granatum) is punicalagin, while walnut (Juglans regia L.) and pecan (C. illinoinensis) contain pedunculagin as the main ellagitannin [178]. ...
... In particular, in pomegranate, ellagitannins are mainly found in the pericarp, bark, seeds, and flowers, while gallotannins are contained mostly in leaves [179]; species of the genera Caesalpinia, Quercus, Myroxylon, Rhus, Prosopis, and others also contain both ellagitannins and gallotannins [167]; young oak leaves contain mostly ellagitannins, and oak bark yields a mixture of ellagitannins and condensed tannins (proanthocyanidins) [154]. Ellagitannins are also found in oak-aged wines as a result of their leakage from the oak barrel into the wine [178]. ...
... In addition to the free form of EA, which enters the body with plant food, the major portion of this compound can arise in the digestive tract of humans and animals as a result of the hydrolytic degradation of ellagitannins present in foodstuffs. Therefore, EA content can be used to indirectly quantify ellagitannins present in plant foods and also as a biomarker of dietary bioavailability of ellagitannins [178,208]. Studies on animal models and human volunteers consuming ellagitannin-rich food have shown that hydrolysis of ellagitannins and EA release occurs in the stomach and/ or small intestine [209,210]. Ester bonds in ellagitannins are relatively slowly hydrolyzed, resulting in prolonged gastrointestinal secretion of EA [211]. ...
Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate (Punica granatum L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various in vitro and in vivo model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.
... The mechanisms of action underlying the biological activities of ETs are not fully elucidated even at present. The hypothesis first launched by Cerdá et al. [81] in 2005 is still supported. According to it, urolithins and/or their possible phase II conjugates formed in vivo are responsible for the biological activities of dietary ETs. ...
... According to it, urolithins and/or their possible phase II conjugates formed in vivo are responsible for the biological activities of dietary ETs. Their anti-cancer, antiinflammatory, cardio-metabolic, antioxidant, and neuroprotective effects [20,25,81] have been demonstrated following in vitro testing, but the in vivo studies are still limited [25,45]. ...
Ellagitannins (ETs) are a large group of bioactive compounds found in plant-source foods, such as pomegranates, berries, and nuts. The consumption of ETs has often been associated with positive effects on many pathologies, including cardiovascular diseases, neurodegenerative syndromes, and cancer. Although multiple biological activities (antioxidant, anti-inflammatory, chemopreventive) have been discussed for ETs, their limited bioavailability prevents reaching significant concentrations in systemic circulation. Instead, urolithins, ET gut microbiota-derived metabolites, are better absorbed and could be the bioactive molecules responsible for the antioxidant and anti-inflammatory activities or anti-tumor cell progression. In this review, we examined the dietary sources, metabolism, and bioavailability of ETs, and analyzed the last recent findings on ETs, ellagic acid, and urolithins, their intestinal and brain activities, the potential mechanisms of action, and the connection between the ET microbiota metabolism and the consequences detected on the gut–brain axis. The current in vitro, in vivo, and clinical studies indicate that ET-rich foods, individual gut microbiomes, or urolithin types could modulate signaling pathways and promote beneficial health effects. A better understanding of the role of these metabolites in disease pathogenesis may assist in the prevention or treatment of pathologies targeting the gut–brain axis.
... Most studies on the bioavailability of ellagitannins have involved feeding humans pomegranate juice, which contains punicalin and punicalagin (Fig. 11) (68,407). However, the bioavailability of ellagitannins in raspberries (158), strawberries, walnuts, and oak-aged wines has also been investigated (69). ...
... In a further study in which volunteers ingested 1 liter of pomegranate juice containing 4.37 g of punicalagins on a daily basis for 5 days, circulating urolithin levels reached a concentration of 18.6 lM (68). Feeding human subjects a single dose of strawberries, raspberries, walnuts, and oak-aged red wine, all of which contain ellagitannins, resulted in excretion of urolithin A 3-O-glucuronide in quantities equivalent to 2.8% (strawberries), 3.4% (raspberries), 6.5% (oak-aged red wine), and 16.6% (walnuts) of intake (69). ...
... Cerdá first discovered Uro A (Uro-A) in 2005 (Cerdá et al. 2005a). In the same year, Uro was suggested as a potential biomarker for the intake of foods rich in ETs (Cerdá, Tomás-Barberán, and Espín 2005b). According to Sigma-Aldrich Chemie GmbH, Uro-A is insoluble in water and methanol, and its solubility in DMSO is 20 mg/mL. ...
... Monomeric ETs can be polymerized to form oligomeric or polymeric ETs. Of course, in addition to the HHDP group, there are other groups that can also be coupled to the glucose core, for example, Gallic acid (present in Casuarictin, Tellimagradin II, Corilagin, Geraniin, Sanguiin H-5, lambertianin B, Sanguiin-H6, and lambertianin C) (Talcott and Lee 2002;Cerdá, Tomás-Barberán, and Espín 2005b;Hager et al. 2008;Mattia et al. 2013;Li et al. 2018), dehydrohexahydroxydiphenyl (present in Geraniin) (Li et al. 2018), Valoneoyl (present in Vescalagin, Castalagin, and Castalin) (Saucier et al. 2006;Patrizia et al. 2014;Akter et al. 2021), Gallagyl (present in Punicalin, and Punicalagin) (Cerdá et al. 2003;Fischer, Carle, and Kammerer 2011). These groups form the ETs family through changes in number and coupling sites. ...
Foods rich in ellagic tannins are first hydrolyzed into ellagic acid in the stomach and small intestine, and then converted into urolithins with high bioavailability by the intestinal flora. Urolithin has beneficially biological effects, it can induce adipocyte browning, improve cholesterol metabolism, inhibit graft tumor growth, relieve inflammation, and downregulate neuronal amyloid protein formation via the β3-AR/PKA/p38MAPK, ERK/AMPKα/SREBP1, PI3K/AKT/mTOR signaling pathways, and TLR4, AHR receptors. But differences have been reported in urolithin production capacity among different individuals. Thus, it is of great significance to explore the biological functions of urolithin, screen the strains responsible for biotransformation of urolithin, and explore the corresponding functional genes. Tannin acyl hydrolase can hydrolyze tannins into ellagic acid, and the genera Gordonibacter and Ellagibacter can metabolize ellagic acid into urolithins. Therefore, application of "single bacterium", "single bacterium + enzyme", and "microflora" can achieve biotransformation of urolithin A. In this review, the source and metabolic pathway of ellagic tannins, and the mechanisms of the biological function of a metabolite, urolithin A, are discussed. The current strategies of biotransformation to obtain urolithin A are expounded to provide ideas for further studies on the relationship between urolithin and human health.
... 18,139,140 Ellagitannins are not absorbed in the gut lumen as such but are metabolized by intestinal flora into urolithins. 141,142 Caco-2 cell studies with ellagic acid, complexed in the form of ellagitannins, have shown that AP-BL transport across the cell membrane is very low. 143 Anthocyanins are colorful water-soluble pigments, found extensively in blue, red, and purple berries. ...
Natural products, such as herbal medicinal products, food supplements, and functional food, are widely used to support well-being and for promoting health. In general, the effects of using these products are desired and beneficial, but unexpected adverse effects might also occur, especially when natural products are used with medication. Consumers do not often even know that they are exposed to bioactive compounds that might interact with the body and have effects on their well-being. One of the objectives of the World Health Organization is to promote herb–drug interaction monitoring, and it is important to know how marketed preparations and compounds from common foods interact when they are absorbed. In this review, we describe how a Caco-2 cell absorption model has been used to study how natural products, such as flaxseed, rapeseed, purple loosestrife, pine, echinacea, certain berries and herbs, anthranoid laxatives, and traditional medicinal plants, affect the absorption of co-administered drugs. We discuss the types of interactions and adverse effects that might occur and their possible reasons. Overall, we conclude that the Caco-2 cell absorption model is a useful tool for studying the absorption of natural products with drugs; and that to enable the safe use of natural products with medicines, concomitant use should be studied.
... Walnut fruit is a plant that contains a high amount of phytochemicals (33,34) In addition, the fruit of the walnut contains high amounts of omega-3 and omega-6 fatty acids. These omega-3 fatty acids are known to have neuroprotective and antioxidant effects (35). ...
... Important phenolic acids in strawberries are the ellagitannins and ellagic acid glucosides, which break down to pure ellagic acid, which is also present in the fruit [88]. Ellagic acid is valuable to human health because it is antimutagenic and has anticarcinogenic activities against chemical-induced cancers [89]. ...
Strawberries (Fragaria x ananassa Duchesne) belong to the berry group and are characterized primarily by delightful sensory properties. Due to their chemical composition, these fruits are a rich source of bioactive compounds that can modify the metabolic and physiological functions of the body. The aim of this work is to present the current state of research on bioactive ingredients found in these fruits in the context of their health-promoting properties. The paper presents compiled and reviewed data on the content of polyphenolic compounds, organic acids, and vitamins, especially vitamin C, in strawberries. The content of these compounds is influenced by many different factors that are discussed in the paper. It also draws attention to the presence of oxalates and allergenic compounds, which are classified as anti-nutritional compounds of strawberries.
... Urolithins are secondary polyphenol metabolites generated via the activity of gut bacteria on ellagitannins (ET) and ellagic acid-rich foods, such as pomegranates, raspberries, strawberries, and walnuts [241]. The acid hydrolysis of ellagitannins releases free ellagic acid [242], which is further processed by gut microbiota that converts ellagic acid into urolithins [238]. ...
Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.
... The way by which hydrolysable tannins are associated with the food matrix has not yet been established. In addition, no information about individual tannins was obtained, as the current method for their determination causes tannin depolymerization [53][54][55]. ...
In the past few years, numerous studies have investigated the correlation between polyphenol intake and the prevention of several chronic diseases. Research regarding the global biological fate and bioactivity has been directed to extractable polyphenols that can be found in aqueous-organic extracts, obtained from plant-derived foods. Nevertheless, significant amounts of non-extractable polyphenols, closely associated with the plant cell wall matrix (namely with dietary fibers), are also delivered during digestion, although they are ignored in biological, nutritional, and epidemiological studies. These conjugates have gained the spotlight because they may exert their bioactivities for much longer than extractable polyphenols. Additionally, from a technological food perspective, polyphenols combined with dietary fibers have become increasingly interesting as they could be useful for the food industry to enhance technological functionalities. Non-extractable polyphenols include low molecular weight compounds such as phenolic acids and high molecular weight polymeric compounds such as proanthocyanidins and hydrolysable tannins. Studies concerning these conjugates are scarce, and usually refer to the compositional analysis of individual components rather than to the whole fraction. In this context, the knowledge and exploitation of non-extractable polyphenol-dietary fiber conjugates will be the focus of this review, aiming to access their potential nutritional and biological effect, together with their functional properties.
... Urolithins are better absorbed than ellagitannins and are thus transported to peripheral tissues or excreted through the urine [5,38,66]. Studies have shown urolithins to be valid biomarkers of walnut consumption [63,67,68] with higher concentrations of the metabolite found 12 h or longer following walnut ingestion [69]. ...
Among all tree nuts, walnuts contain the highest total polyphenols by weight. This secondary data analysis examined the effect of daily walnut supplementation on the total dietary polyphenols and subclasses and the urinary excretion of total polyphenols in a free-living elderly population. In this 2-year prospective, randomized intervention trial (ID NCT01634841), the dietary polyphenol intake of participants who added walnuts daily to their diets at 15% of daily energy were compared to those in the control group that consumed a walnut-free diet. Dietary polyphenols and subclasses were estimated from 24 h dietary recalls. Phenolic estimates were derived from Phenol-Explorer database version 3.6. Participants in the walnut group compared to the control group had a higher intake of total polyphenols, flavonoids, flavanols, and phenolic acids in mg/d (IQR): 2480 (1955, 3145) vs. 1897 (1369, 2496); 56 (42,84) vs. 29 (15, 54); 174 (90, 298) vs. 140 (61, 277); and 368 (246, 569) vs. 242 (89, 398), respectively. There was a significant inverse association between dietary flavonoid intake and urine polyphenol excretion; less urinary excretion may imply that some of the polyphenols were eliminated via the gut. Nuts had a significant contribution to the total polyphenols in the diet, suggesting that a single food like walnuts added to habitual diet can increase the polyphenol intake in a Western population.
... 2,3 Nevertheless, while ETs and EA absorption is low, they are further metabolized by the colonic microbiota to urolithins (Uros), which are responsible, at least partially, for the beneficial effects of ETs-and (or) EA-rich foods. 1,4 First, EA is released through the hydrolysis of ETs' ester bonds by the enzyme known as ellagitannase. 5 EA undergoes further degradation, producing 6H-dibenzo[b,d]pyran-6-one derivatives called Uros. ...
Urolithin (Uro) production capacity and, consequently, at least partly, the health effects attributed to ellagitannin and ellagic acid consumption vary among individuals. The reason is that not all individuals have the gut bacterial ecology needed to produce the different Uro metabolites. Three human urolithin metabotypes (UM-A, UM-B, and UM-0) based on dissimilar Uro production profiles have been described in populations worldwide. Recently, the gut bacterial consortia involved in ellagic acid metabolism to yield the urolithin-producing metabotypes (UM-A and UM-B) in vitro have been identified. However, the ability of these bacterial consortia to customize urolithin production to mimic UM-A and UM-B in vivo is still unknown. In the present study, two bacterial consortia were assessed for their capacity to colonize the intestine of rats and convert UM-0 (Uro non-producers) animals into Uro-producers that mimic UM-A and UM-B, respectively. Two consortia of Uro-producing bacteria were orally administered to non-urolithin-producing Wistar rats for 4 weeks. Uro-producing bacterial strains effectively colonized the rats' gut, and the ability to produce Uros was also effectively transferred. Bacterial strains were well tolerated. No changes in other gut bacteria, except Streptococcus reduction, or adverse effects on haematological and biochemical parameters were observed. Besides, two novel qPCR procedures were designed and successfully optimized to detect and quantify Ellagibacter and Enterocloster genera in faecal samples. These results suggest that the bacterial consortia are safe and could be potential probiotics for human trials, which is especially relevant for UM-0 individuals, who cannot produce bioactive Uros.
... Urolithin A is a benzocoumarin metabolite produced by the gut microbiome by digestion of ellagic acid and ellagitannins found in dietary pomegranates, strawberries, raspberries and wallnuts. Urolithin A does not occur free in dietary foods and is not produced by mammalian enzyme systems.345,346 Urolithin A is a natural pro-biotic that promotes mitophagy, mitochondrial biogenesis and metabolic function impacting on muscle health in preclinical models of aging and in the elderly and middle-aged. ...
Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti‐oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain‐relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration. Animal models of IVD deneration have yielded invaluable information on the pathobiology of this degenerative condition and identified prospective therapeutic targets.The complexity of the degenerative changes and multiple therapeutic targets identified by these models suggests artificial intelligence methodology may be required to unravel these complexities and provide a rationale way forward in the development of effective repair strategies.
... One such metabolite is urolithin A (UA). UA is produced in the colon when gut bacteria break down ellagitannins, natural compounds which are found in edible plants such as pomegranates, strawberries, and walnuts [18]. Numerous studies have shown that UA robustly improves mitochondrial activity, muscle function, lifespan, and cognition in several animal models [19][20][21]. ...
In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with potential neuroprotec-tive activity. WT and 3xTg-AD mice were administered long-term intermittent dietary supplementation with UA. UA was found to prevent deficits in spatial memory, cued fear response, and exploratory behavior in this model. It also decreased the Aβ plaque burden in areas of the hippocampus where these protein deposits are prominent in the model. Interestingly, correlation analyses demonstrate that Aβ plaque burden positively correlates with enhanced spatial memory in 3xTg-AD mice on a control diet but not in those supplemented with UA. In contrast, Aβ42 abundance in cortical and hippocampal homogenates negatively correlate with spatial memory in UA-fed mice. Our data suggest that plaque formation may be a protective mechanism against neurodegeneration and cognitive decline and that targeting the generation of proteotoxic Aβ species might be a more successful approach in halting disease progression. UA was also found to extend lifespan in normal aging mice. Mech-anistically, we demonstrate that UA is able to induce autophagy and to increase Aβ clearance in neuronal cell lines. In summary, our studies reveal UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition in the 3xTg-AD mouse model as well as extending lifespan in normal aging mice.
... Although the (poly)phenol metabolome in isolated lipoproteins remains poorly studied, levels of individual metabolites (PCA, DHPP and hippuric acid) reported in this study are within the range of values reported earlier for tyrosol-based metabolites (240 pmol/mg ApoB-100 protein) in LDL of healthy women [60]. Overall values of (poly)phenol metabolites ranged between 100 nM and 21 μM (Supplementary Table 2) which are within plasma values reported in healthy individuals following intermittent [31,32,61] and sustained (poly)phenol-rich diets [62][63][64]. ...
The incidence of diabetes on the worldwide population has tripled in the past 5 decades. While drug-based therapies are valuable strategies to treat and ease the socio-economic burden of diabetes, nutritional strategies offer valuable alternatives to prevent and manage diabetes onset and contribute to the sustainability of health budgets. Whilst, intervention studies have shown that (poly)phenol-rich diets improve fasting glucose levels and other blood parameters, very little is known about the distribution of ingested polyphenols in circulation and the impact of diabetes on its cargo.
In this study we investigate the impact of type 2 diabetes on the cargo of plasma (poly)phenols. Our results show that phenolic compounds are heterogeneously distributed in circulation though mainly transported by lipoprotein populations. We also found that diabetes has a marked effect on the phenolic content transported by VLDL resulting in the decrease in the content of flavonoids and consequently a decrease in the antioxidant capacity. In addition to the reduced bioavailability of (poly)phenol metabolites and increase of oxidative status in LDL and HDL populations in diabetes, cell-based assays show that sub-micromolar amounts of microbial (poly)phenol metabolites are able to counteract the pro-inflammatory status in glucose-challenged endothelial cells.
Our findings highlight the relevance of triglyceride-rich lipoproteins in the transport and delivery of bioactive plant-based compounds to the endothelium in T2DM supporting the adoption of nutritional guidelines as an alternative strategy to drug-based therapeutic approaches.
... It has been established that the gut microbiota is responsible for the conversion of ETs into secondary metabolites such as EA and urolithins (Bialonska et al., 2009;Cheng et al., 2017;Piwowarski et al., 2016). EA is absorbed moderately and metabolized by gut microbiota into urolithins which are then absorbed in the intestine (Cerdá et al., 2005;Espín et al., 2007). It is plausible that the health benefits observed after consuming food rich in ETs is because of these gut metabolites rather than the parent polyphenols. ...
Ellagitannin-rich food has been implicated to ameliorate cardiovascular risk, particularly blood pressure (BP). This systematic review and meta-analysis investigated the effect of ellagitannin-rich fruit consumption on BP. Five databases were screened and RCTs reporting the effect of ellagitannin-rich fruit consumption on BP and polyphenol content were included. Nineteen studies with 1,249 participants, showed a non-significant systolic blood pressure (SBP) and significant diastolic blood pressure (DBP) reduction, with ET-rich fruit consumption. Subgroup analysis revealed significant SBP reduction among hypertensives receiving 500–1000 mg polyphenol (-4.95 mmHg, 95 % CI: [-7.24, −2.66]) and among metabolic syndrome (MS) patients (-3.44 mmHg; 95 % CI: [-5.25, −1.63]). meta-regression revealed a positive association between polyphenol dosage and SBP changes. In conclusion, the consumption of ellagitannin-rich fruits may be considered an anti-hypertensive functional food/drink and recommended for patients who are at high risk for hypertension. Further well-designed trials are required to resolve the significant heterogeneities identified in the current literature.
... Red, violet, purple or blue colour is due to the presence of antioxidants in them that enhance human health. Many authors focus their studies on proving the biological activity in raspberry fruits that has anticancer, antibacterial, antiviral, anti-inflammatory and cardiovascular disease prevention (Wang, 2000;Moyer et al., 2002;Mullen et al., 2003;Cerda et al., 2005;Seeram et al., 2006;Jakobek et al., 2007;Heinonen, 2007;Borges et al., 2007) The purpose of the present article is to follow the impact of some elements of raspberry cultivation technology on the biochemical composition and quality of the fruit. ...
The biochemical composition of raspberry fruit was studied at two different planting distances. Their qualitative
characteristics were determined. The impact of an individual technological element on the studied indicators was
analysed. The experiment included raspberry cultivars, such as 'Willamette', 'Meeker', 'Samodiva' and a candidate
cultivar 'Magdalena' from the collection plantation of RIMSA-Troyan. The planting material was produced in vitro. The
planting distances were: 0.30 m and 0.50 m in the intra row spacing and 3.00 m in the row spacing. The highest amount
of anthocyanins (38.87 mg) and total polyphenols (263.37 mg%) were reported for 'Willamette' fruit at 0.50 m planting
distances. The highest antioxidant activity was reported in 'Willamette' fruit (7750.00 µmol TE/100 g) (at 0.30 m) and
'Samodiva' (6625.00 µmol TE/100 g) (at 0.50 m). The sensor rating is in the range from 4.63 ('Willamette' - 0.50 m) to
4.93 ('Magdalena' candidate cultivar - 0.30 m).
... and Lactobacillus-Enterococcus spp. [308,309]. Similarly, cornelian cherry promotes the development of prebiotic microorganisms with a similar detrimental effect on the growth of potentially pathogenic microorganisms [310,311]. This reciprocal influence further supports the hypothesis of a prominent gastrointestinal activity of herbal plants that could inhibit the α-glucosidase enzyme before systemic absorption and, in parallel, improve the microbiota system contributing to a "healthy" gut microbiota [312]. ...
Data on urban and rural diabetes prevalence ratios show a significantly lower presence of diabetes in rural areas. Several bioactive compounds of plant origin are known to exert anti-diabetic properties. Interestingly, most of them naturally occur in different plants present in mountainous areas and are linked to traditions of herbal use. This review will aim to evaluate the last 10 years of evidence-based data on the potential anti-diabetic properties of 9 plants used in the Piedmont Alps (North-Western Italy) and identified through an ethnobotanical approach, based on the Occitan language minority of the Cuneo province (Sambucus nigra L., Achillea millefolium L., Cornus mas L., Vaccinium myrtillus L., Fragaria vesca L., Rosa canina L., Rubus idaeus L., Rubus fruticosus/ulmifolius L., Urtica dioica L.), where there is a long history of herbal remedies. The mechanism underlying the anti-hyperglycemic effects and the clinical evidence available are discussed. Overall, this review points to the possible use of these plants as preventive or add-on therapy in treating diabetes. However, studies of a single variety grown in the geographical area, with strict standardization and titration of all the active ingredients, are warranted before applying the WHO strategy 2014–2023.
... 61 Ellagitannins are large molecules with limited bioavailability and they are metabolized by hydrolysis to ellagic acid, which is converted into two lactones, urolithins A and B, 3,8-dihydroxy-6H-dibenzopyran-6-one and its monohydroxylated analog. 62 ...
This chapter discusses Microbial Metabolism of Polyphenols and Health
... One such metabolite is urolithin A (UA). UA is produced in the colon when gut bacteria break down ellagitannins, natural compounds which are found in edible plants such as pomegranates, strawberries and walnuts (18). Numerous studies have shown that UA robustly improves mitochondrial activity, muscle function, lifespan and cognition in several animal models (19)(20)(21). ...
In recent years, a burgeoning body of evidence has pointed to age-related dysfunction in neuronal autophagy as playing a prominent role in neuropathology associated with Alzheimer’s disease (AD). In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with potential neuroprotective activity. WT and 3xTg-AD mice were administered long-term intermittent dietary supplementation with UA. UA was found to prevent deficits in spatial memory, cued fear response and exploratory behavior in this model. It also decreased the Aβ plaque burden in areas of the hippocampus where these protein deposits are prominent in the model. Interestingly, correlation analyses demonstrate that Aβ plaque burden positively correlates with enhanced spatial memory in 3xTg mice on a control diet but not in those supplemented with UA. In contrast, Aβ42 abundance in cortical and hippocampal homogenates negatively correlate with spatial memory in UA-fed mice. Our data suggest that plaque formation may be a protective mechanism against neurodegeneration and cognitive decline and that targeting the generation of proteotoxic Aβ species might be a more successful approach in halting disease progression than targeting plaque formation. UA was also found to extend lifespan in normal aging mice. Mechanistically, we demonstrate that UA is able to induce autophagy and to increase Aβ clearance in neuronal cell lines. In summary, our studies reveal UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition the 3xTg AD mouse model as well as extending lifespan in normal aging mice.
... Metabolomics is interesting to the nutrition community as a free-living, objective dietary assessment tool (138,139). Biomarkers of intake have been found for various foods, such as bread (140), coffee (141), citrus consumption (142), and meat and fish (143), as well as dietary components such as polyphenols (144,145) and fermented foods (146). Such information can be used not only for simply monitoring food intake but also for associations with health and disease outcomes (141,142,147). ...
Data currently generated in the field of nutrition is becoming increasingly complex and high-dimensional, bringing with it new methods of data analysis. The characteristics of machine learning make it suitable for such analysis and thus lends itself as an alternative tool to deal with data of this nature. Machine learning has already been applied in important problem areas in nutrition such as obesity, metabolic health, and malnutrition. Despite this, experts in nutrition are often without an understanding of machine learning, which limits its application and therefore potential to solve currently open questions. Thus, the current article aims to bridge this knowledge gap by supplying nutrition researchers with a resource to facilitate the use of ML in their research. Machine learning is first explained and distinguished from existing solutions, with key examples of applications in the nutrition literature provided. Two case studies of domains in which machine learning is particularly applicable, precision nutrition and metabolomics, are then presented. Finally, a framework is first outlined to guide the interested researcher in integrating machine learning into their work. By acting as a resource to which researchers can refer, we hope to support the integration of machine learning in the field of nutrition to facilitate modern research.
... Asimismo, el ácido elágico ejerce un efecto protector indirecto contra el estrés oxidante mediante la regulación positiva de Nrf-2 y la regulación negativa de Keap1, modulando la inducción de las enzimas antioxidantes como SOD, CAT, GPx, GST e incrementando los niveles de GSH mediante la regulación positiva de la GSH sintetasa (Ding De manera importante, se ha sugerido que los posibles beneficios para la salud que brindan los elagitaninos y el ácido elágico se deben a la actividad de las urolitinas, ya que tienen una mayor tasa de absorción, una vida media plasmática (tiempo necesario para eliminar el 50% del fármaco administrado del organismo) más prolongada y alcanzan niveles micromolares en la circulación sistémica y los tejidos periféricos; potenciando los efectos antioxidantes (Cerda et al., 2005). ...
Pomegranate (Punica granatum L.) is a fruit rich in bioactive compounds with various biological properties that help maintain good health. In particular, the polyphenolic compounds punicalagin, ellagic acid, urolithins and gallic acid are among the main molecules with antioxidant potential identified in this fruit; that is, these compounds have the ability to prevent cellular alterations caused by oxidative stress and/or induce the body's own antioxidant response to protect cells. As a result, numerous scientific studies have emerged in the last decade, focused on recognizing the pharmacological properties of these molecules, to prevent the development and progression of diseases in which oxidative stress plays a fundamental role. The objectives of this review are: 1) to point out the importance of antioxidants obtained from the diet and in particular those obtained from pomegranate, 2) to highlight the beneficial effects of ellagitannins, ellagic acid, urolithins and gallic acid against various pathologies, and 3) recognize that despite their potential as therapeutic agents, further research in humans is required to promote their use in the clinic.
... In contrast to the poor absorption of ETs and EA, relevant (in the low micromolar range) concentrations of Uros, mainly as phase-II conjugates, can circulate in the bloodstream and reach systemic tissues (García-Villalba et al., 2022). This is why Uros were early proposed by Cerdá et al. (2005) as the "missing link" to explain the paradoxical low bioavailability of ETs and the health benefits described upon consuming ET-containing foods. Nowadays, the most relevant Uros can be obtained commercially, and show potential multitarget in vivo activities, scarcely investigated compared to other metabolites García-Villalba et al., 2022). ...
Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial signatures , ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection.
... However, it exhibits limited bioavailability in vivo because of its flat structure-induced low solubility (10). Usually, EA can be hydrolyzed and metabolized by gut microbiota to generate dibenzopyran-6-one derivatives, called as urolithins such as urolithin M5 (UM5), urolithin M6 (UM6), urolithin A (UA), and urolithin B (UB) that are easily absorbed into blood circulation (11). EA has been recognized posing potential neuroprotective effects by its anti-inflammation, anti-oxidation, and anti-neurotoxicity properties (12). ...
Ellagic acid (EA) is a dietary polyphenol that widely exists in grapes, strawberries, and walnuts. It usually exerts multiple biological activities together with its in vivo metabolites called urolithins. EA and urolithins had been proposed as natural agents for applying on the early intervention of Alzheimer’s disease (AD). However, the neuroprotective effects of those small molecules have not been confirmed, and the action mechanism is not clear. Deposition of beta-amyloid (Aβ) protein is well documented as being involved in the initiation and pathological process of AD. In the present study, we investigated the attenuating effects of EA and several urolithins on Aβ25–35-induced neuronal injury and its underlying molecular mechanism by constructing the in vitro AD cell model of PC12 cells and primary neurons. The results revealed that EA and urolithins especially the UM5 and UM6 exerted promising neuroprotective effects in improving the Aβ25–35-induced cell damage and lactate dehydrogenase (LDH) leakage, reducing reactive oxygen species (ROS) production, inhibiting neuronal apoptosis, and promoting neurite outgrowth. These results provide new insights into the development of UM5 and UM6 as anti-AD candidates. A network pharmacology analysis combining molecular docking strategy was further adopted to predict the signaling pathway involved in the anti-AD action of EA and urolithins, and the activation of PI3K-Akt, as well as the inhibition of MAPK was found to be involved.
... UroA production is not uniform among individuals who consume comparable amounts of EA/ET-rich foods due to the presence/absence and varied levels of UroAproducing bacteria in each individual [26]. Independent studies in healthy volunteers suggested that only 40-50% of humans were capable of producing UroA following pomegranate juice or walnut consumption [27][28][29][30][31][32][33][34][35][36][37]. Andreux et al [38] showed that oral consumption of UroA in a human phase 1 study of healthy or sedentary elders either as a single dose or as multiple doses (500 mg or 1000 mg daily) over a 4-weeks is not toxic. ...
The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers.
Methods: We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both in vitro and in vivo models. The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods. Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors.
Results: Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments. Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU. Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis. Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice.
Conclusions: In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy. This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.
Keywords: Chemoresistant colon cancer, 5-Fluorouracil, Microbial metabolite, Urolithin A, Chemosensitization, drug transporters, FOXO3-FOXM1 axis
... Ellagitannins are hexahydroxydiphenic acid esters, likely derived from a gallotannin precursor (i.e., penta-O-galloyl-β-D-glucose), and are found in pomegranates, strawberries, raspberries, blackberries, peaches, plums, wines, and various nuts [108][109][110]. The most relevant sources of ellagitannins for pigs are walnuts and acorns, which are included in feed in some Mediterranean countries and a significant amount of research has focused on assessment of their digestibility, nutritional effects and potential positive health outcomes [104,111]. ...
Polyphenolic compounds have a variety of functions in plants including protecting them from a range of abiotic and biotic stresses such as pathogenic infections, ionising radiation and as signalling molecules. They are common constituents of human and animal diets, undergoing extensive metabolism by gut microbiota in many cases prior to entering circulation. They are linked to a range of positive health effects, including anti-oxidant, anti-inflammatory, antibiotic and disease-specific activities but the relationships between polyphenol bio-transformation products and their interactions in vivo are less well understood. Here we review the state of knowledge in this area, specifically what happens to dietary polyphenols after ingestion and how this is linked to health effects in humans and animals; paying particular attention to farm animals and pigs. We focus on the chemical transformation of polyphenols after ingestion, through microbial transformation, conjugation, absorption, entry into circulation and uptake by cells and tissues, focusing on recent findings in relation to bone. We review what is known about how these processes affect polyphenol bioactivity, highlighting gaps in knowledge. The implications of extending the use of polyphenols to treat specific pathogenic infections and other illnesses is explored.
... Among EAderived metabolites, urolithin A is the major metabolite that is discovered in fecal matter in human beings (Gonzalez-Barrio et al., 2011;Jayatunga et al., 2021). The amount of EA in the peripheral tissues and systemic circulation is virtually paltry, while urolithins and their conjugates can extend to concentrations at the micromolar point (Cerda et al., 2005). Plasma levels of EA after the intake of vegetables and fruits (normal plasma concentrations of 0.1-0.4 ...
Ellagic acid (EA), a naturally occurring polyphenolic compound, is detected in free form or linked to polyols or sugars, constituting hydrolyzable tannins or ellagitannins in distinct fruits, nuts, and herbs. Today, a considerable number of botanicals and enriched foods containing EA are commercially available as nutraceuticals and used to prevent mild cognitive impairment (MCI) due to the excellent neuroprotective capacity of EA. Here, this study aims to provide an overview of the physicochemical properties, source, and pharmacokinetics of EA and to emphasize the importance and mechanisms of EA in the prevention and management of MCI. To date, preclinical studies of EA and its derivatives in various cell lines and animal models have advanced the idea of dietary EA as a feasible agent capable of specifically targeting and improving MCI. The molecular mechanisms of EA and its derivatives to prevent or reduce MCI are mainly through reducing neuroinflammation, oxidative stress, neuronal apoptosis, synaptic dysfunction and loss, and defective mitochondrial functions. Nevertheless, well-designed and correctly large randomized controlled trials in the human population need to be performed to reinforce the scientific facticity of the beneficial effects of EA against MCI. Synchronously, the mechanism of EA against MCI is least provided cynosure and expects more attention from the emerging research community.
... Ellagitannin (ETs) are known as hydrolysable tannins which are found from strawberries, raspberries, walnuts, pomegranate, oakaged red wine etc. [13]. Larrosa et al. [14] provide evidence that ETs and their hydrolysis product Ellagic Acid (EA) induce apoptosis in tumour cells. ...
Since the dawn of time, plants have been employed as therapeutic agents. The high expense and severe side effects of conventional chemotherapy have lowered public acceptance and fueled the hunt for alternatives. Alternative therapy methods, such as phytochemicals, have become more widely available and cost-effective. Loss of mitochondrial membrane potential, release of cytochrome-c, and other processes and pathways are all involved in the anticancer activity of plant- derived therapeutic substances. Anti-apoptotic proteins are down regulated, while pro-apoptotic proteins are up-regulated. Caspase, Fas, FADD, p53, and c-Jun signaling pathways are activated; Akt signaling pathway is inhibited; phosphorylation of ERK, P13K, Raf, survivin gene, STAT 3, and NF-kB is inhibited. In-vitro testing of skin cancer cell lines models allows researchers to discover the mechanisms of action of chemicals derived from plants against a variety of skin malignancies. As a result, the goal of this study is to provide an overview of plant-derived anti-cancer chemicals that have been found to have promising anti-carcinogenic activities.
... Urolithins have been found in many animals such as mice, rats, beavers, sheep, cattle and humans after eating foods rich in ETs (31,32). Recently, urolithinproducing microorganisms have also been reported. ...
There are trillions of microorganisms in the human intestine. They can react to the intestinal microenvironment by metabolizing food or producing small molecular compounds to affect the host's digestive ability and resist the risk of infection and autoimmune diseases. Many studies have revealed that intestinal flora and its metabolites play an important role in human physiology and the development of diseases. Urolithins are kind of intestinal microbiota metabolites of ellagitannins (ETs) and ellagic acid (EA) with potent biological activity in vivo. However, different individuals have different intestinal flora. According to the different metabolites from ETs and EA, it is divided into three metabo-types including UM-A, UM-B and UM-0. This paper reviews the origin of urolithins, the urolithin producing microorganisms and the effects of urolithins on regulating intestinal diseases. This review will provide a theoretical basis for the regulation of urolithins in the homeostasis of intestinal flora and a reference for the scientific utilization of urolithins and foods rich in ETs and EA.
... At the same time, fermentation produces useful substrates (e.g., SCFAs and probably other still unknown metabolites) for the microbial counterpart, in a sort of prebiotic effect. In contrast, hydrolyzable tannins are degraded in mild acid conditions, releasing the monomers of gallic or ellagic acid directly in the upper digestive tract, which then undergo adsorption, conjugation with methyl, glucuronic or sulfate groups and finally excretion [144]. ...
Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds.
... ETs are a complex class of bioactive compounds, mainly comprised of hydrolyzed tannins, found in pomegranates, strawberries, ground elm, blueberries, raspberries, tea, walnuts, chestnuts and mulberries (Cerdá et al., 2005). The consumption of ETs has been consistently associated with positive effects towards many pathologies, including metabolic disorders and diabetes (El-Missiry et al., 2015;Atrahimovich et al., 2018). ...
Urolithin (Uro) B is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranates, raspberries, blueberries and chestnuts. Uro B has recently garnered considerable attention owing to its wide range of nutraceutical effects and relatively high potency. According to several studies, Uro B prevents the development of hyperlipidemia, cardiovascular disease (CVD) and tumors due to its strong antioxidant and anti-inflammatory properties. Many reviews have systematically summarized the health benefits and pharmacological activities of ETs, EA and urolithins (especially Uro A) while available reviews or detailed summaries on the positive impact of Uro B are rarer. Here, we sought to review the pharmacological activity, mechanism of action, regulation of immune function and its associated diseases and preventive potential of Uro B to elucidate its function as a nutritional agent in humans.
... UroA production is not uniform among individuals who consume comparable amounts of EA/ET-rich foods due to the presence/absence and varied levels of UroAproducing bacteria in each individual [26]. Independent studies in healthy volunteers suggested that only 40-50% of humans were capable of producing UroA following pomegranate juice or walnut consumption [27][28][29][30][31][32][33][34][35][36][37]. Andreux et al [38] showed that oral consumption of UroA in a human phase 1 study of healthy or sedentary elders either as a single dose or as multiple doses (500 mg or 1000 mg daily) over a 4-weeks is not toxic. ...
Colon cancer is the third leading cause in cancer related deaths in United States of America. Chemoresistance (drug resistance) of tumors is the primary reason for the failure of chemotherapy and a major cause of mortality in colon cancer. The molecular mechanisms involved in chemoresistance or methods to chemosensitization of cancer cells to chemotherapy remain elusive. Recent studies suggest that gut microbiota and microbial metabolites play a crucial role in the development and progression of colon cancer. Urolithin A (UroA) is a gut microbial metabolite derived from ellagitannin/ellagic acid rich-diets such as pomegranate and berries. Here, we identified that UroA and its novel structural analogue (UAS03) chemosensitize 5FU resistant (5FUR) colon cancer cells to 5FU treatment. Our data suggested that combination of 5FU with UroA or UAS03 significantly reduced cell viability of 5FUR colon cancer cell lines with combination index (CI) less than 1 suggesting their synergism. Moreover, UroA or UAS03 in combination with 5FU significantly inhibited 5FUR colon cancer cell proliferation, migration as well as induced apoptosis. Mechanistically, UroA or UAS03 treatment down regulated drug transporters (MDR1, BCRP and MRP2) leading to decreased efflux of drug (e.g., 5FU) and potentially responsible for chemosensitization. Furthermore, treatment with these compounds also modulated EMT makers (e.g., downregulated Snail and β-catenin; upregulated ZO-1 and E-cadherin) to reduce EMT transition. Treatment of UroA or UAS03 in combination with 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Taken together, utilization of UroA or UAS03 in combination with 5FU treatment may provide better therapeutic options for 5FUR colon cancer alleviation.
Citation Format: Sweta Ghosh, Rajbir Singh, Zachary M. Vanwinkle, Haixun Guo, Praveen K. Vemula, Ajay Goel, Bodduluri Haribabu, Venkatakrishna Rao Jala. Microbial metabolite, Urolithin A acts as chemo-sensitizing adjuvant in conventional drug therapies via modulation of drug transporters and EMT markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3250.
... The health benefits of tannins include antioxidant, anti-carcinogenic, cardioprotective, antimutagenic, antiviral, antibacterial, haemostatic, and anti-inflammatory properties, as well as inhibition of lipid perioxidation [45,46] Hydrolysable tannins are often cited for their antimicrobial activity [46] and chemopreventive properties against degenerative diseases [50]. These multi-functional properties of tannins are utilised in the treatment of human diseases [51]. ...
Cryopreservation and storage of semen for artificial insemination (AI) result in excessive accumulation of reactive oxygen species (ROS). This leads to a shortened life span and reduced motility of spermatozoa post-thawing, with consequent impairment of their function. However, certain levels of ROS are essential to facilitate the capacitation of spermatozoa required for successful fertilisation. Tannins, as well-known antioxidant compounds, may act as ROS binders/acceptors/scavengers to inhibit the damaging effects of ROS. This review comprises an analysis of the semen cryopreservation protocol and health functions of tannins, as well as the effects of ROS on fresh and cryopreserved semen’s longevity and fertilisation. Additionally, we surveyed available evidence of the effects of tannin extract feed supplementation on male fertility. We furthermore interrogated existing theories on tannin use as a potential additive to semen extenders, its relationship with semen quality, and to what degree existing theories have been investigated to develop testable new hypotheses. Emphasis was placed on the effects of tannins on ROS, their involvement in regulating sperm structure and function during cryopreservation, and on post-thaw sperm motility, capacitation, and fertilising ability. The diverse effects of tannins on the reproductive system as a result of their potential metal ion chelation, protein precipitation, and biological antioxidant abilities have been identified. The current data are the first to support the further investigation of the incorporation of tannin-rich plant extracts into semen extenders to enhance the post-thaw survival, motility, and fertilising ability of cryopreserved spermatozoa.
Berries are rich in (poly)phenols, and these compounds may be beneficial to human health. Estimating berry consumption through self-reported questionnaires has been challenging due to compliance issues and a lack of precision. Estimation via food-derived biomarkers in biofluids was proposed as a complementary alternative. We aimed to review and update the existing evidence on biomarkers of intake for six different types of berries. A systematic literature search was performed to update a previous systematic review on PubMed, Web of Science, and Scopus from January 2020 until December 2022. Out of 42 papers, only 18 studies were eligible. A multimetabolite panel is suggested for blueberry and cranberry intake. Proposed biomarkers for blueberries include hippuric acid and malvidin glycosides. For cranberries, suggested biomarkers are glycosides of peonidin and cyanidin together with sulfate and glucuronide conjugates of phenyl-γ-valerolactone derivatives. No new metabolite candidates have been found for raspberries, strawberries, blackcurrants, and blackberries. Further studies are encouraged to validate these multimetabolite panels for improving the estimation of berry consumption.
Non-communicable diseases, such as cardiovascular disease, cancer, diabetes, obesity, and hypertension, represent the cause of 60% of all deaths around the globe. With proper diet and natural dietary antioxidant supplements, these diseases can be prevented by up to 40% according to the British Nutrition Foundation.
This book provides a comprehensive overview of the literature on the health benefits of natural dietary antioxidant supplements. It presents state-of-the-art research and information as well as the global regulations, labelling, and health claims of natural dietary antioxidant supplements.
Written by expert authors, the wealth of research is arranged by disease type rather than by supplement type making it much more useful to the reader. Filling a gap in the literature, the book is aimed at researchers and professionals working in food chemistry, nutrition, and health benefits.
The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in rapid clearance within the intestinal tract, limiting systemic exposure and subsequent AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that functionally increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA), a gut bacterial metabolite of ellagitannins, as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). In mice, dietary exposure to UroA in a 10% broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in the liver. Thus, CYP1A1 dietary competitive substrates can lead to enhanced systemic AHR ligand distribution from the gut, likely through the lymphatic system, increasing AHR activation in key barrier tissues. Finally, this report will lead to a reassessment of the dynamics of distribution of other hydrophobic chemicals present in the diet.
Backgound/Objectives
Urolithins (UROs) are the metabolites derived from the gut microbial action on ellagitannins and ellagic acid-rich foods. Following their absorption in the intestine, UROs are transported through the systemic circulation to various tissues where they can express their biological function as antimicrobial, anti-inflammatory, and anticancer agents. In addition to blood plasma, where they can be found as glucuronide and sulfate conjugates, they are also found in urine. Therefore, the interactions of UROs with serum proteins are of great clinical interest.
Methods
A powerful technique for examining these urolithin-serum protein interactions is fluorescence spectroscopy. Bovine serum albumin (BSA) is a particularly suitable model protein because it is readily available, affordable, and similar to human serum albumin. This work aimed to study the binding of UROs (urolithin A, UROA and urolithin B, UROB) and their glucuronide conjugates (UROAG and UROBG) to BSA by quenching the intrinsic fluorescence of protein.
Results
The spectra obtained showed that the binding process is influenced by the polyphenol's structure and the conjugation process with the glucuronide. The calculated Stern Vollmer binding constants (K sv ): UROA and UROB K sv were 59236 ± 5706 and 69653 ± 14922, respectively, while for UROAG and UROBG, these values were 15179 ± 2770 and 9462 ± 1955, respectively, which showed that the binding affinity decreased with glucuronidation. Molecular docking studies confirmed that all of the studied molecules will bind favorably to BSA. The preferential binding site for both UROs and UROGs is Sudlow I, while UROs will also bind to Sudlow II. URO-Gs can bind to BSA in the cleft region with lower binding scores than for the Sudlow I binding site.
Conclusion
The aglycone's higher hydrophobicity increases the binding affinity to BSA, thus reducing its bioavailability in the blood.
Most of the pertinent research which aims at exploring the therapeutic effects of polyphenols usually misapprehends a large fraction of non-extractable polyphenols due to their poor aqueous-organic solvent extractability. These polymeric polyphenols (i.e., proanthocyanins, hydrolysable tannins and phenolic acids) possess a unique property to adhere to the food matrix polysaccharides and protein sowing to their structural complexity with high glycosylation, degree of polymerization, and plenty of hydroxyl groups. Surprisingly resistance to intestinal absorption does not hinder its bioactivity but accelerates its functionality manifolds due to the colonic microbial catabolism in the gastrointestinal tract, thereby protecting the body from local and systemic inflammatory diseases. This review highlights not only the chemistry, digestion, colonic metabolism of non-extractable polyphenols (NEPP) but also summarises the synergistic effect of matrix-bound NEPP exerting local as well as systemic health benefits.
Nonalcoholic fatty liver disease (NAFLD) is a worldwide prevalent chronic liver disease characterized by hepatic steatosis. Water caltrop, the fruit of Trapa natan, is widely cultivated as an edible vegetable in Asian countries. In China, water caltrop pericarp has long been used as a functional food to treat metabolic syndrome, yet the bioactive substances and their pharmacological mechanisms remain unclear. In this study, a natural gallotannin, 1,2,3,6-tetra-O-galloyl-β-D-glucopyranoside (GA), was isolated from water caltrop pericarp and evaluated for its therapeutic effect on NAFLD. Treatment of GA (15 and 30 mg/kg/day) suppressed the body weight gain (p < 0.001) and ameliorated lipid deposition (p < 0.001) in high-fat diet (HFD)-induced NAFLD mice. GA was able to alleviate HFD-induced insulin resistance (p < 0.001), oxidative stress (p < 0.001), and inflammation (p < 0.001), thereby restoring the liver function in HFD-induced NAFLD mice. Mechanistically, GA diminished the aberrant signaling pathways including AMPK/SREBP/ACC, IRs-1/Akt, IKK/IκB/NF-κB in HFD-induced NAFLD mice and modified gut microbiota dysbiosis in these mice as well. The current findings suggest that GA is a promising novel agent for NAFLD therapy.
Over the past few decades, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (ATO) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, ATO has become the frontline treatments for patients with APL. However, its therapeutic applicability is severely constrained by ATO-induced cardiac side effects. Any cardioprotective agents that can ameliorate the cardiac side effects and allow exploiting the full therapeutic potential of ATO, undoubtedly gain significant attention. The knowledge and use of natural products for evidence-based therapy have grown rapidly in recent years. Here we discussed the potential mechanism of ATO-induced cardiac side effects and reviewed the studies on cardiac side effects as well as the research history of ATO in the treatment of APL. Then, We summarized the protective effects and underlying mechanisms of natural products in the treatment of ATO-induced cardiac side effects. Based on the efficacy and safety of the natural product, it has a promising future in the development of cardioprotective agents against ATO-induced cardiac side effects.
The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in the rapid clearance within the intestinal tract, limiting AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA) as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). Dietary exposure to UroA in a broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in liver. Thus, CYP1A1 dietary competitive substrates can lead to intestinal escape, likely through the lymphatic system, increasing AHR activation in key barrier tissues.
Urolithins are the gut microbiota metabolites of ellagitannins which are found in natural plants such as pomegranate, strawberry, and raspberry, and in nuts. Recently, several reports have clarified the underlying mechanism of urolithins in central nervous system inflammation. Therefore, urolithins have become potential therapeutic drug candidate molecules for central nervous system diseases. Derivatives 1–1d, 1–1f, 3–2a, and 3–2b of urolithin A, urolithin B, and methoxyurolithin A were found to have had significant inhibitory activity against phosphodiesterase II with IC 50 values of 35.42, 39.96, 25.58, and 13.84 μM, respectively. Herein, we report the design and synthesis of urolithin derivatives along with a biological evaluation of their activity against phosphodiesterase II.
Oxidative stress is a major cellular and metabolic burden that can really alter cell life and became the base for disease inset and development. Many widespread pathologies can develop starting from an unresolved oxidative stress situation, thus addressing this state is paramount for human health. Our antioxidant enzymes sometimes are not just enough. Fortify our defense and antioxidant and anti-inflammatory system can make a difference for our health: if this attainable with our dietary habits, could be a dream come true. Polyphenols are a fantastic tool indeed into the fight against oxidative stress: they are easy to obtain, with little cost, no side effects, and a multitude of metabolic actions. This perspective review would like to shed a light about polyphenol's metabolic and molecular action respect to oxidative stress to help us to preserve our health.
Background
In recent years, a burgeoning body of evidence has pointed to age-related dysfunction in neuronal autophagy as playing a prominent role in neuropathology associated with Alzheimer’s disease (AD). In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with potential neuroprotective activity.
Methods
WT and 3xTg-AD mice were administered long-term intermittent dietary supplementation with UA. Following evaluation of spatial learning and memory, associative learning and exploratory behavior, we employed fluorescence-based immunodetection of human Aβ42 + Aβ40 to determine Aβ plaque deposition and quantified Aβ42 in hippocampal and cortical homogenates via sandwich ELISA in 14-months old mice. Using neuronal cell types, we analyzed the effects of UA on the expression of autophagy genes and proteins and on lysosomal acidification. We treated mouse hippocampal cells with Aβ oligomers while inducing autophagy with UA and analyzed Aβ clearance.
Results
UA was found to prevent behavioral deficits in this model. It also decreased the Aβ plaque burden in areas of the hippocampus where these protein deposits are prominent in the model. Interestingly, correlation analyses demonstrate that Aβ plaque burden positively correlates with enhanced spatial memory in 3xTg mice on a control diet but not in those supplemented with UA. In contrast, Aβ42 abundance in cortical and hippocampal homogenates negatively correlate with spatial memory in UA-fed mice. UA was also found to extend lifespan in normal aging mice. Mechanistically, we demonstrate that UA is able to induce autophagy and to increase Aβ clearance in neuronal cell lines.
Conclusions
In summary, our data suggest that plaque formation may be a protective mechanism against neurodegeneration and cognitive decline and that targeting the generation of proteotoxic Aβ species might be a more successful approach in halting disease progression than targeting plaque formation. UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition the 3xTg AD mouse model as well as extending lifespan in normal aging mice.
Oxidative stress and inflammation are two possible mechanisms related to nephrotoxicity caused by environmental pollutants. Ellagic acid, a powerful antioxidant phytochemical, may have great relevance in mitigating pollutant-induced nephrotoxicity and preventing the progression of kidney disease. This review discusses the latest findings on the protective effects of ellagic acid, its metabolic derivatives, the urolithins, against kidney toxicity caused by heavy metals, pesticides, mycotoxins, and organic air pollutants. We describe the chelating, antioxidant, anti-inflammatory, antifibrotic, antiautophagic, and antiapoptotic properties of ellagic acid to attenuate nephrotoxicity. Furthermore, we present the molecular targets and signaling pathways that are regulated by these antioxidants, and suggest some others that should be explored. Nevertheless, the number of reports is still limited to establish the efficacy of ellagic acid against kidney damage induced by environmental pollutants. Therefore, additional preclinical studies on this topic are required, as well as the development of well-designed clinical trials.
1. Pomegranate peel polyphenols (PPPs) have anti-oxidation, anti-atherosclerosis, anti-obesity effects, and so on. However, few studies have been conducted on the absorption and transformation of pomegranate polyphenols in the gut and the biologically active forms that ultimately work in the body.
2. In this study, PPPs (300 mg/kg/day) was given to normal rats and relatively sterile rats by gavage respectively. The relatively sterile rats were obtained by neomycin sulphate (250 mg/kg/day) gavage to rats. The purpose of this study is to elaborate on the relationship between intestinal flora and polyphenol metabolism of pomegranate peel and to quantitatively analyse the transformation process of its metabolite urolithin in rats.
3. The results showed that decreased bacterial diversity could significantly reduce the abundance of PPPs metabolites in faeces and urine in relatively sterile rats. PPPs can regulate intestinal flora structure, significantly enhance the content of Clostrida Firmicutes (P < 0.05), and effectively promote acetic acid, propionic acid, butyric acid, iso-butyric acid and valeric acid production in the rat (P < 0.05 or P < 0.01 or P < 0.001). PPPs can significantly elevate the relative proportion of Ruminococcaceae (P < 0.05). Ruminococcaceae_NK4A214_group, Ruminococcaceae_UCG-014 and Ruminococcaceae_UCG-005 can promote the metabolic transformation of PPPs and make the utilisation of Urolithin A more effective.
Recent clinical studies demonstrated that certain natural polyphenols like flavonoids present in dietary supplements modify the pharmacokinetics of some co-administered drugs. Number of herbal remedies interact selectively with different CYP450 isoenzymes and hence alter CYP- mediated drug metabolism and pharmacokinetics. Drug-polyphenol interaction may alter drug bio availability through altered absorption, distribution and metabolism. There is need to collect clinical evidences to support whether the effect of
drugs and polyphenols co-administration rather than relying on in-vitro experiments or animal studies. Herbal drugs containing variety of polyphenols interact with CYP450 enzymes leading to either induction or inhibition of CYPs which alters the pharmacokinetic parameters of their respective substrate drugs. This information will be helpful for physicians and pharmacists to alleviate risks associated with polyphenolic
remedies as well as to realize the benefits of alternative medicine.
Introduction
This review concerns three species of berries, namely, the high-latitude cloudberry (Rubus chamaemorus) and arctic bramble (Rubus arcticus), and the high-altitude yellow raspberry (Rubus ellipticus). These plants are mostly exploited on a local basis as food or traditional remedies but could have a wider usage as nutraceuticals due to their richness in ellagitannins (ETs) and other phenolic compounds. ETs are hexahydroxydiphenoyl esters of carbohydrates and the largest group of hydrolysable tannins. They are distinctly antioxidant and bioactive compounds, and therefore, are considered as the major responsible for the biological properties of ET-rich berries. The health benefits of ETs are mainly due to the release of ellagic acid and to their metabolic transformation by the gut microbiota into urolithins, and include, among others, anti-inflammatory, antiviral, anti-bacterial, and anticancer actions.
Methods
Based on the literature searches in the Web of Science, Scopus, and PubMed databases, ethnobotanical, pharmaceutical, medicinal, and nutritional knowledge concerning the three berry species was covered. This includes empirical use of traditional preparations and experimental studies with various extracts and fractions from fruits and other plant portions, covering in vitro, preclinical, and clinical research.
Results
The complex of data reveals a wide spectrum of potential uses in health care, providing in some cases an experimental confirmation of traditional uses.
Conclusions
The examined berry species can act as nutraceutical food producing positive effects on regular consumers but could also be exploited in more technological ways to produce food complements from ET-rich extracts.
A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the esophageal-specific carcinogen, N-nitrosomethylbenzylamine (NMBA) in the F344 rat esophagus. Phenylpropyl isothiocyanate (PPITC) was more potent than either phenylethyl isothiocyanate (PEITC) or benzyl isothiocyanate (BITC). Phenylbutyl isothiocya-nate (PBITC), however, had a lesser inhibitory effect on esopha-geal tumorigenesis, and phenylhexyl isothiocyanate (PHITC) actually enhanced esophageal tumorigenesis. Thus, the two-and three-carbon isothiocyanates were more effective inhibitors of NMBA-esophageal carcinogenesis than the longer chain isothio-cyanates. The effects of the isothiocyanates on tumorigenesis were well correlated as to their effects on DNA adduct formation. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome P450 enzymes responsible for the metabolic activation of NMBA in rat esophagus. A freeze-dried strawberry preparation was also evaluated for its ability to inhibit NMBA-esophageal tumorigenesis. It proved to be an effective inhibitor, although not as potent as either PEITC or PPITC. The inhibitory effect of the berries could not be attributed solely to the content of the chemopreventive agent, ellagic acid, in the berries.
The content of ellagic acid was determined from the berries of the family Rosaceae (strawberry, red raspberry, cloudberry, arctic bramble). Extraction and hydrolysis procedures were optimized and analysis
was done with an HPLC method and UV detection. The influence of processing on ellagic acid content was studied in strawberry
jam. Strawberries, red raspberries, and strawberry jam were analyzed fresh and after 3, 6, and 9 months of storage in a domestic
freezer or refrigerator. Ellagic acid contents after 3 months of storage at −20 °C varied between 31.5 (strawberry ‘Senga
Sengana’) and 68.6 mg/100 g f.w. (arctic bramble). Ellagic acid content in strawberry jam (23.8 mg/100 g f.w.) was 80% of
that in unprocessed strawberries. The content of ellagic acid in strawberries and red raspberries was reduced by 40% and 30%,
respectively, during the 9 months of storage at −20°C. The unprocessed berries studied, together with nuts, make the main
contribution to the total dietary intake of ellagic acid in Finland.
To take advantage of the various pharmacologic activities of soy bean isoflavones, more detailed studies of the absorption and excretion rates of these compounds in humans and subsequent evaluation of their bioavailabilities are required. We conducted a pharmacokinetic study of soybean isoflavones in seven healthy male volunteers. After ingestion of 60 g of kinako (baked soybean powder, containing 103 micromol daidzein and 112 micromol genistein), changes of the isoflavone and metabolite concentrations in plasma, urine and feces were measured by gas chromatography-mass spectrometry. The plasma concentration of genistein increased after 2 h and reached its highest value of 2.44 +/- 0.65 micromol/L 6 h later. The plasma concentration of daidzein peaked at 1.56 +/- 0.34 micromol/L at the same time, but it was always lower than that of genistein. Peak plasma concentration of O-desmethylangolensin (O-DMA) and equol appeared after the daidzein peak in four and two subjects, respectively. In contrast with plasma, daidzein was the main component in urine. Urinary daidzein excretion started to increase shortly after the rise in its plasma concentration and reached 2.4 micromol/h 8 h after ingestion of kinako. Genistein excretion in urine paralleled that of daidzein, but the value at 6 h was about half (1.1 micromol/h). The majority of ingested isoflavones after ingestion of kinako were recovered on d 2 or 3 in the feces. Total recovery of daidzein, O-DMA and equol from urine and feces was 54.7%, calculated from daidzein intake; 20.1% of administered genistein was recovered as genistein. The half-lives of plasma genistein and daidzein were 8.36 and 5.79 h, respectively. The individual plasma and urinary concentrations of equol and O-DMA were quite variable; subjects were classified as high and low metabolizers. The high plasma concentration of isoflavones for at least several hours after a single ingestion of soy protein suggests that these compounds may interact with macromolecules and have biological effects.
A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the esophageal-specific carcinogen, N-nitrosomethylbenzylamine (NMBA) in the F344 rat esophagus. Phenylpropyl isothiocyanate (PPITC) was more potent than either phenylethyl isothiocyanate (PEITC) or benzyl isothiocyanate (BITC). Phenylbutyl isothiocyanate (PBITC), however, had a lesser inhibitory effect on esophageal tumorigenesis, and phenylhexyl isothiocyanate (PHITC) actually enhanced esophageal tumorigenesis. Thus, the two- and three-carbon isothiocyanates were more effective inhibitors of NMBA-esophageal carcinogenesis than the longer chain isothiocyanates. The effects of the isothiocyanates on tumorigenesis were well correlated as to their effects on DNA adduct formation. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome P450 enzymes responsible for the metabolic activation of NMBA in rat esophagus. A freeze-dried strawberry preparation was also evaluated for its ability to inhibit NMBA-esophageal tumorigenesis. It proved to be an effective inhibitor, although not as potent as either PEITC or PPITC. The inhibitory effect of the berries could not be attributed solely to the content of the chemopreventive agent, ellagic acid, in the berries.
Polymeric proanthocyanidins are common constituents of many foods and beverages. Their fate in the human body remains largely unknown. Their metabolism by human colonic microflora incubated in vitro in anoxic conditions has been investigated using nonlabeled and (14)C-labeled purified proanthocyanidin polymers. Polymers were almost totally degraded after 48 h of incubation. Phenylacetic, phenylpropionic and phenylvaleric acids, monohydroxylated mainly in the meta or para position, were identified as metabolites by gas chromatography coupled to mass spectrometry (GC-MS). Yields were similar to those previously reported for flavonoid monomers. These results provide the first evidence of degradation of dietary phenolic polymers into low-molecular-weight aromatic compounds. To understand the nutritional properties of proanthocyanidins, it is therefore essential to consider the biological properties of these metabolites.
Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis, which is promising considering the limited number of chemopreventives with this potential.
Dietary flavonoids may protect against cardiovascular disease, but evidence is still conflicting. Tea is the major source of flavonoids in Western populations.
The association of tea and flavonoid intake with incident myocardial infarction was examined in the general Dutch population.
A longitudinal analysis was performed with the use of data from the Rotterdam Study-a population-based study of men and women aged >or=55 y. Diet was assessed at baseline (1990-1993) with a validated semiquantitative food-frequency questionnaire. The analysis included 4807 subjects with no history of myocardial infarction, who were followed until 31 December 1997. Data were analyzed in a Cox regression model, with adjustment for age, sex, body mass index, smoking status, pack-years of cigarette smoking, education level, and daily intakes of alcohol, coffee, polyunsaturated fat, saturated fat, fiber, vitamin E, and total energy.
During 5.6 y of follow-up, a total of 146 first myocardial infarctions occurred, 30 of which were fatal. The relative risk (RR) of incident myocardial infarction was lower in tea drinkers with a daily intake >375 mL (RR: 0.57; 95% CI: 0.33, 0.98) than in nontea drinkers. The inverse association with tea drinking was stronger for fatal events (0.30; 0.09, 0.94) than for nonfatal events (0.68; 0.37, 1.26). The intake of dietary flavonoids (quercetin + kaempferol + myricetin) was significantly inversely associated only with fatal myocardial infarction (0.35; 0.13, 0.98) in upper compared with lower tertiles of intake.
An increased intake of tea and flavonoids may contribute to the primary prevention of ischemic heart disease.
Epidemiologic studies report inconsistent findings on the association of fruit and vegetable intake with the risk of cardiovascular disease.
The objective was to examine the relation between fruit and vegetable intake and the risk of cardiovascular disease.
We studied 9608 adults aged 25-74 y participating in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study and free of cardiovascular disease at the time of their baseline examination between 1971 and 1975. Fruit and vegetable intake at baseline was measured with a food-frequency questionnaire. The incidence of and mortality from cardiovascular disease were obtained from medical records and death certificates.
Over an average of 19 y, 888 strokes (218 fatal), 1786 ischemic heart disease events (639 fatal), 1145 cardiovascular disease deaths, and 2530 all-cause deaths were documented. Consuming fruit and vegetables > or = 3 times/d compared with <1 time/d was associated with a 27% lower stroke incidence [relative risk (RR): 0.73; 95% CI: 0.57, 0.95; P for trend = 0.01), a 42% lower stroke mortality (0.58; 0.33, 1.02; P for trend = 0.05), a 24% lower ischemic heart disease mortality (0.76; 0.56, 1.03; P for trend = 0.07), a 27% lower cardiovascular disease mortality (0.73; 0.58, 0.92; P for trend = 0.008), and a 15% lower all-cause mortality (0.85; 0.72, 1.00; P for trend = 0.02) after adjustment for established cardiovascular disease risk factors.
We showed an inverse association of fruit and vegetable intake with the risk of cardiovascular disease and all-cause mortality in the general US population.
Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. It is exclusively a product of intestinal bacterial metabolism of dietary isoflavones and it possesses estrogenic activity, having affinity for both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other isoflavones in its antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, it is relatively stable; however, equol is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol by establishing that maximal clinical responses to soy protein diets are observed in people who are good "equol-producers." It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions. In reviewing the history of equol, its biological properties, factors influencing its formation and clinical data, we propose a new paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol. The failure to distinguish those subjects who are "equol-producers" from "nonequol producers" in previous clinical studies could plausibly explain the variance in reported data on the health benefits of soy.
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases such as cancer and cardiovascular diseases is emerging. The health effects of polyphenols depend on the amount consumed and on their bioavailability. In this article, the nature and contents of the various polyphenols present in food sources and the influence of agricultural practices and industrial processes are reviewed. Estimates of dietary intakes are given for each class of polyphenols. The bioavailability of polyphenols is also reviewed, with particular focus on intestinal absorption and the influence of chemical structure (eg, glycosylation, esterification, and polymerization), food matrix, and excretion back into the intestinal lumen. Information on the role of microflora in the catabolism of polyphenols and the production of some active metabolites is presented. Mechanisms of intestinal and hepatic conjugation (methylation, glucuronidation, sulfation), plasma transport, and elimination in bile and urine are also described. Pharmacokinetic data for the various polyphenols are compared. Studies on the identification of circulating metabolites, cellular uptake, intracellular metabolism with possible deconjugation, biological properties of the conjugated metabolites, and specific accumulation in some target tissues are discussed. Finally, bioavailability appears to differ greatly between the various polyphenols, and the most abundant polyphenols in our diet are not necessarily those that have the best bioavailability profile. A thorough knowledge of the bioavailability of the hundreds of dietary polyphenols will help us to identify those that are most likely to exert protective health effects.
The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18−20 TEAC) three times higher than those of red wine and green tea (6−8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12−14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500−1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices. Keywords: Pomegranate; Punica granatum; Punicaceae; juice; phenolics; anthocyanins; ellagic acid; punicalagin; tannins; antioxidant activity; ABTS; DPPH; DMPD; FRAP
The occurrence of ellagitannins in common foodstuffs is limited to a few fruit and nut species. Dietary intake of ellagitannins is largely explained by the consumption of strawberries, raspberries and blackberries. No reliable figures are available for the ellagitannin burden, but it will probably not exceed 5 mg day−1. Their bioavailability is not well defined. A fraction of the ellagitannins ingested is hydrolysed in the gut and the resulting ellagic acid absorbed and metabolised, but whether intact ellagitannins are absorbed is not clear. There are apparently conflicting claims for beneficial and toxic effects caused by ellagitannins, ellagic acid or ellagitannin-containing extracts in various animal species including rodents and ruminants. It seems unlikely that normal consumption can cause toxic effects in man, but any attempt to increase the intake significantly in pursuit of the suggested benefits should be resisted until the metabolism and pharmacokinetics are better understood.© 2000 Society of Chemical Industry
We previously showed that ellagic acid (EA) was inhibiting lung tumorigenesis induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. In the present study, we observed that the inhibition of lung tumorigenesis was independent of the solvent used to purified EA. Pomegranate peels extract containing punicalagin (alpha and beta anomers) (10 g/kg diet) and oligomeric anthocyanins (6 g/kg diet) did not inhibit lung tumorigenesis. Raspberry extract (2x15 mg) containing sanguiin H6 and lambertianin D as well as oligomeric procyanidins (2x15 mg) inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity by about 30%. The same treatments inhibit TPA-stimulated hydroperoxide (HPx) production by about 30 and 70%. Raspberry ellagitannins and oligomeric procyanidins respectively inhibit TPA stimulated DNA synthesis by 42 and 26%. Our results su est that hydrolyzable and condensed tannins from various sources, which can inhibit the ODC, HPx, and DNA responses to TPA, might also inhibit the tumor-promoting activity of this agent. The results of this study show that EA and ellagitannins have different antitumorigenic and antipromoting activities.
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Ellagic acid and gallic acid and its derivatives, applied topically to female CF-1 mice 20 min before each 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment inhibit the inductions of epidermal ornithine decarboxylase activity, hydroperoxide production and DNA synthesis caused by this potent tumor promoter in relation with their abilities to inhibit the promotion of skin papillomas and carcinomas in the two-step initiation-promotion protocol. Because of its potency against TPA promotion, tannic acid, which is already known to inhibit tumor initiation, may inhibit the multistage process of carcinogenesis.
This study was undertaken to measure the liberation in vitro of ellagic acid [2], a naturally occurring inhibitor of carcinogenesis, from precursor ellagitannins under conditions found in the gut tract. Enzymes, namely beta-glucosidase, esterases, and alpha-amylase, were incubated with raspberry extract. In addition, raspberry extract and casuarictin [1] were treated at different pH's and with the contents of small intestine and cecum from rats fed AIN-76A diet. The esterase activity of the enzyme samples was measured spectrophotometrically using p-nitrophenol acetate as the substrate, and the amount of ellagic acid [2] released from all samples was analyzed by hplc. The hydrolysis of the ellagitannins was not catalyzed by any of the purified enzymes tested, and components of the raspberry extract were found to inhibit the purified esterases noncompetitively. Casuarictin [1] was hydrolyzed to yield high quantities of ellagic acid [2] when placed in buffer at pH 7 and 8, or when incubated with cecal contents for two hours. The release of ellagic acid [2] from the raspberry extract was optimal at pH 8, and maximal release in cecal contents occurred with 1 h. Small intestinal contents had no significant effect on ellagic acid liberation from either casuarictin [1] or raspberry extract.
1. Following oral administration of ellagic acid to the rat, 10% of the dose was excreted as 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one in urine and faeces. A second metabolite was detected in urine and faeces but not identified. Both metabolites were of microfloral origin, as their formation was not observed in germ-free rats but was demonstrated when ellagic acid was incubated in vitro with micro-organisms from rat gastro-intestinal tract. 2. Following intraperitoneal, but not oral, administration of ellagic acid, a third metabolite was detected in urine. 3. Unchanged ellagic acid was not detected in faeces or urine of any normal rat examined, but small amounts were detected in the faeces of germ-free animals. 4. Following oral administration of ellagic acid, two conjugates of 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one were detected in bile, whereas intraperitoneal administration resulted in the biliary excretion of three conjugates of an unidentified metabolite.
The flavonoid quercetin, or its metabolites, inhibit chemical carcinogenesis in rodents and may have a role in the prevention of human cancers. Quercetin exposure in human populations results from the dietary intake of various plant foods; high concentrations of quercetin are found in apples, onions, tea, and red wine. Determination of the relationship between dietary intake and cancer risk depends on the characterization of quercetin intake. The development and use of biomarkers for quercetin intake may provide a basis for the objective classification of this exposure. One possible biomarker is metabolic products of quercetin. We report the development of a high-performance liquid chromatography (HPLC)-based assay for quantitation of quercetin metabolites in human urine. The metabolites include 3,4-dihydroxyphenylacetic acid (homoprotocatechuic acid), metahydroxyphenylacetic acid, and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid). The assay has only two major steps, ether extraction and HPLC analysis, and is suitable for analysis of large sample numbers. Analytical characteristics of the assay include a sensitivity of less than 1 microgram, precision with coefficients of variation < 10%, and metabolite recoveries > 90%. The mean concentrations of 3,4-dihydroxyphenylacetic acid, metahydroxyphenylacetic acid, and homovanillic acid in two human urine samples are approximately 0.7, 4.8, and 2.8 micrograms/ml, respectively. The identification of each metabolite is confirmed by HPLC, UV absorbance scans, and gas chromatography-mass spectrometry analysis. These results verify the occurrence of quercetin metabolites in human urine and the feasibility of quercetin metabolite quantitation, by the assay described herein, for epidemiological studies. Development of the analytical procedure is an essential first step for validation of the metabolites as biomarkers of quercetin intake.
Bioassay-guided fractionation of the MeOH extract of Pteropi faeces (the feces of Trogopterus xanthipes Milne-Edwards) furnished three hyaluronidase inhibitory active 6H-dibenzo[b,d]-pyran-6-ones (1-3), together with a new compound, 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one (4). Their structures were established on the basis of the spectroscopic methods.
Terminalia catappa L. is a popular folk medicine for preventing hepatoma and treating hepatitis in Taiwan. In this paper, we examined the protective effects of T. catappa leaf water extract (TCE) and its major tannin component, punicalagin, on bleomycin-induced genotoxicity in cultured Chinese hamster ovary cells. Pre-treatment with TCE or punicalagin prevented bleomycin-induced hgprt gene mutations and DNA strand breaks. TCE and punicalagin suppressed the generation of bleomycin-induced intracellular free radicals, identified as superoxides and hydrogen peroxides. The effectiveness of TCE and punicalagin against bleomycin-induced genotoxicity could be, at least in part, due to their antioxidative potentials.
Hydrolyzable tannins showed higher cytotoxic activity against human oral squamous cell carcinoma and salivary gland tumor cell lines than against normal human gingival fibroblasts, whereas gallic acid, a component unit of tannins, showed much weaker selective cytotoxicity. The cytotoxic activity of dimeric compounds was generally higher than that of monomeric compounds. Macrocyclic ellagitannin oligomers, such as oenothein B, woodfordin C and woodfordin D showed the greatest cytotoxic activity, and their activity (per given number of molecules) was one order higher than those of gallic acid and epigallocatechin gallate, a major component of green tea. These compounds induced apoptotic cell death characterized by DNA fragmentation (as demonstrated by the TUNEL method) and cleavage of cytokeratin 18 by activated caspase(s) (as demonstrated by M30 monoclonal antibody). ESR spectroscopy revealed that these macrocyclic compounds at higher concentrations produced their own radicals and significantly enhanced the radical intensity of sodium ascorbate, possibly by their prooxidant actions. Catalase failed to eliminate their apoptosis-inducing activity, reducing the possibility of the involvement of hydrogen peroxide production in the extracellular fraction. These observations suggested that the antitumor activity of macrocyclic ellagitannin oligomers reported previously might be explained by their apoptosis-inducing activity.
The intake of flavonols, flavones and isoflavones by Japanese women was calculated from our food-phytochemical composition table. The relationship between intake of these phytochemicals and various anthropometric and blood chemistry data was analyzed in a cross-sectional study. The subjects were 115 women volunteers, aged 29-78 y, living in the northern part of Japan. Each subject completed a 3-d dietary record and received a health check up, including urine and blood sampling for biochemical analysis. Total mean intakes of flavonoids (sum of flavonols and flavones) and isoflavones were 16.7 and 47.2 mg/d, respectively. The major source of flavonoids was onions (45.9%) and that of isoflavones was tofu (37.0%). Total intake of isoflavones exceeded that of other dietary antioxidants, such as flavonoids, carotenoids (3.5 mg/d) and vitamin E (8.2 mg/d), and was approximately one half of the vitamin C intake (109 mg/d). The total intake of flavonoids was inversely correlated with the plasma total cholesterol concentration (TC) (r = -0.236, P: < 0.05) and plasma LDL cholesterol concentration (LDL-C) (r = -0.220, P: < 0.05), after the adjustment for age, body mass index and total energy intake. As a single component, quercetin was inversely correlated with both TC (r = -0.261, P: < 0.01) and LDL-C (r = -0. 263, P: < 0.01). Among Japanese, flavonoid and isoflavone intake is the main component among nonnutrient phytochemicals with antioxidant potential in the diet. These results suggest that a high consumption of both flavonoids and isoflavones by Japanese women may contribute to their low incidence of coronary heart disease compared with women in other countries.
The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18-20 TEAC) three times higher than those of red wine and green tea (6-8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12-14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500-1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices.
The purpose of this study was to investigate biomarkers of the bioavailability and metabolism of hydroxycinnamate derivatives through the determination of the pharmacokinetics of their urinary elimination and identification of the metabolites excreted. Coffee was used as a rich source of caffeic acid derivatives and human supplementation was undertaken. The results show a highly significant increase in the excretion of ferulic, isoferulic, dihydroferulic acid (3-(4-hydroxy-3-methoxyphenyl)-propionic acid), and vanillic acid postsupplementation relative to the levels presupplementation. Thus, ferulic, isoferulic, and dihydroferulic acids are specific biomarkers for the bioavailability and metabolism of dietary caffeic acid esters. Isoferulic acid is a unique biomarker as it is not a dietary component, however, dihydroferulic acid may well derive from other flavonoids with a structurally related B-ring. 3-Hydroxyhippuric acid has also been identified as an indicator for bioavailability and metabolism of phenolic compounds, and shows a highly significant excretion increase postsupplementation. The results reveal isoferulic acid (and possibly dihydroferulic acid) as novel markers of caffeoyl quinic acid metabolism.
Recent epidemiologic studies have associated nut consumption with a reduced incidence of cardiovascular mortality. However, little is known about the contribution of nut polyphenols to antioxidant and cardiovascular protection. In this investigation, polyphenol-rich extracts from English walnuts (Juglans regia) were studied and compared with ellagic acid for their ability to inhibit in vitro plasma and LDL oxidation, as well as their effects on LDL alpha-tocopherol during oxidative stress. In addition, the Trolox equivalent antioxidant activity (TEAC) was determined and liquid chromatography electrospray detection mass spectrometry (LC-ELSD/MS) analyses of the walnut extracts were performed. 2,2'-Azobis'(2-amidino propane) hydrochloride (AAPH)-induced LDL oxidation was significantly inhibited by 87 and 38% with the highest concentration (1.0 micromol/L) of ellagic acid and walnut extract, respectively. In addition, copper-mediated LDL oxidation was inhibited by 14 and 84% in the presence of ellagic acid and walnut extract, respectively, with a modest, significant LDL alpha-tocopherol sparing effect observed. Plasma thiobarbituric acid reacting substance (TBARS)